Abstract
BackgroundStatins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. However, the relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. We herein examined the influence of the CETP status on the lipid-reducing effects of pitavastatin in hypercholesterolemic patients with type 2 diabetes mellitus as well as the molecular mechanism underlying pitavastatin-induced modifications in CETP levels.MethodsFifty-three patients were treated with 2 mg of pitavastatin for 3 months. Serum levels of LDL-C, small dense (sd) LDL-C, and CETP were measured before and after the pitavastatin treatment. The effects of pitavastatin, T0901317, a specific agonist for liver X receptor (LXR) that reflects hepatic cholesterol contents, and LXR silencing on CETP mRNA expression in HepG2 cells were also examined by a real-time PCR assay.ResultsThe pitavastatin treatment decreased LDL-C, sdLDL-C, and CETP levels by 39, 42, and 23 %, respectively. Despite the absence of a significant association between CETP and LDL-C levels at baseline, baseline CETP levels and its percentage change were an independent positive determinant for the changes observed in LDL-C and sdLDL-C levels. The LXR activation with T0901317 (0.5 μM), an in vitro condition analogous to hepatic cholesterol accumulation, increased CETP mRNA levels in HepG2 cells by approximately 220 %, while LXR silencing markedly diminished the increased expression of CETP. Pitavastatin (5 μM) decreased basal CETP mRNA levels by 21 %, and this was completely reversed by T0901317.ConclusionBaseline CETP levels may predict the lipid-reducing effects of pitavastatin. Pitavastatin-induced CETP reductions may be partially attributed to decreased LXR activity, predictable by the ensuing decline in hepatic cholesterol synthesis.Trial registrationUMIN Clinical Trials Registry ID UMIN000019020
Highlights
Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels
As liver X receptor (LXR) has been identified as a hepatic cholesterol sensor [7], serum CETP levels may be a surrogate for hepatic lipid content [8]
Effects of pitavastatin and T0901317 on the expression of lipid metabolism-related genes in HepG2 cells First, we examined the cytotoxic effects of pioglitazone and T0901317 on HepG2 cells by measuring LDH levels in the supernatants
Summary
Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. The relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. Circulating CETP transfers the cholesterol ester (CE) from low density lipoproteins (LDL) and high density lipoproteins (HDL) to very low density lipoproteins (VLDL) in an equimolecular exchange of triglycerides (TG) according to their concentrations [2]. Dyslipidemia in type 2 diabetes mellitus is characterized by high TG levels, low HDL-C levels, and high sd LDL –C levels [13]. In type 2 diabetes mellitus, the production of TG-enriched VLDL is increased, which readily causes the formation of TG-rich LDL, a precursor of sd LDL [13, 14]. CETP enhances the production of TG-rich LDL due to its functional properties, leading to preferable formation of sd LDL [2, 13]
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